Ординатура / Офтальмология / Английские материалы / Macular Edema A Practical Approach_Coscas, Cunha-Vaz, Loewenstein. Soubrane_2010

Abstract

Macular edema represents a common final pathway for many disease processes. Related ocular disorders include diabetic retinopathy, vascular occlusions, post surgical situations and inherited disorders. The pathophysiology includes breakdown of the blood ocular barrier, release of various cytokines and significant inflammations. These mechanisms may be complicated by ischemic processes. The various pathogenetic mechanisms and their contribution to the edema process are described in detail in this chapter.

Macular edema represents a common final pathway of many intraocular and systemic diseases, which usually involve the retinal vessels.

It typically occurs with painless impairment of visual acuity in one eye but can also be bilateral, depending on the etiology. A macular edema is a nonspecific sign of many ocular disorders (Marmor, 1999; Tranos et al., 2004)1, 2.

Usually the symptoms progress slowly. Nevertheless, while the progression of symptoms is usually slow, the patient may still experience a sudden onset, depending on the etiology.

Normal Retinal Anatomy and Physiology

Definition of Macular Edema

A macular edema is defined as an accumulation of fluid in the outer plexiform layer and the inner

nuclear layer as well as a swelling of the Müller cells of the retina. It consists of a localized expansion of the retinal extracellular space (sometimes associated with the intracellular space) in the macular area.

The macular edema is caused by an abnormal permeability of the perifoveal retinal capillaries resulting in a thickening of the retinal tissue. A macular edema is considered chronic when persisting for more than 6 months.

Different manifestations can be observed: (fig. 1–3):

•perfused (nonischemic or associated with ischemic maculopathy);

•focal, diffuse or nonischemic (perfused).

A cystoid macular edema (CME) is a configuration with radially orientated, perifoveal cystic spaces (Rotsos and Moschos, 2008)4. The central fluid is more prominent in the outer plexiform layer (Henle’s layer). The cysts are characterized by an altered light reflex with a decreased central reflex and a thin, highly reflective edge.

The pseudocysts are areas of the retina in which the cells have been displaced. They are more prominent and widely spread in the inner nuclear layer. Larger cysts are frequently surrounded by smaller peripheral cysts. Occasionally lamellar holes can form (the surface of the cyst elevates and lifts away).

Macular edema is frequently associated with relative ischemia and a broken foveal capillary ring, which can be manifested by fluorescein angiography. The foveal avascular zone may become irregular and enlarged because of nonperfusion of the marginal capillaries. Closure of retinal arterioles may result in larger areas of nonperfusion and progressive ischemia. Evidence of enlargement of the foveal avascular zone greater than 1,000 μm generally indicates visual loss.

In some cases, mainly secondary to vascular occlusion, macular edema may be due to leakage of proteins through vascular walls following intracellular as well as extracellular hypertonic environment development following an ischemic event, similar to the development of brain ischemia (Finkelstein, 1992)5.

The macular area of the retina is predisposed for the development of an edema due to its unique anatomy, which is characterized by the following facts:

•extremely high concentration of cells;

•high metabolic activity;

•the Henle fiber layer courses laterally away from the central fovea;

•potential reservoir for the accumulation of extravascular fluid due to the thickness and loose binding of inner connecting fibers in the outer plexiform layer;

•the central avascular zone creates a watershed arrangement between the choroidal and retinal circulation, thus decreasing resorption of extracellular fluid.

Related Ocular Disorders

Macular edema is a common cause of a sudden and/or chronic decrease in visual acuity occurring in many ophthalmic diseases.

Diabetic Macular Edema

Definition and Classification

Macular edema is the most important complication of diabetes mellitus leading to an impairment of visual acuity (Joussen et al., 2007)6. A diabetic macular edema is defined as a retinal thickening caused by the accumulation of intraretinal fluid and/or hard exudates within 2 disk diameters of the center of the macula, the fovea (fig. 4).

The incidence of diabetic macular edema is closely associated with the degree of diabetic retinopathy and the duration and type of the disease. The 25-year cumulative incidence in persons with type 1 diabetes mellitus is 29% for macular edema and 17% for clinically significant macular edema.

Further data show the incidence of diabetic macular edema for patients whose age at diagnosis was <30 years and who were taking insulin, varied from 0% in those who had diabetes <5 years to 29% in those whose duration of diabetes was 20 years or more.

For patients whose age at diagnosis was >30 years, the rates varied from 3% in those who had diabetes <5 years to 28% in those whose duration of diabetes was 20 years or more.

There are two subtypes of diabetic macular edema, a focal and a diffuse form (Girach and Lund-Andersen, 2007; Klein et al., 2009)7, 8. It also needs to be emphasized that there are slightly different definitions of these two subtypes in the international literature, which use different criteria. The correct classification is important, because the two subtypes have to be treated differently.

Focal macular edema refers to localized areas of retinal thickening, caused by foci of vascular

Fig. 4. Fundus photography of a patient with diabetic retinopathy and diabetic macular edema with exudates.

abnormalities, primarily microaneurysms, and less commonly intraretinal microvascular abnormalities. These have an increased tendency for fluid leakage, which is usually accompanied by hard exudates. The hard exudate pattern can be either focal or (often) ring-shaped.

Diffuse macular edema is caused by a general diffuse leakage from dilated retinal capillaries (and from microaneurysms and arterioles) throughout the posterior pole of the retina. It can usually be observed in both eyes with the degree of leakage being similar or extensively different.

There are also classifications for ischemic and exudative macular edema. In most cases, a hybrid type of these two can be observed.

A clinically significant macular edema is defined by the Early Treatment Diabetic Retinopathy Study to include any of the following features: (1) thickening of the retina at or within 500 μm of the center of the macula; (2) hard exudates at or within 500 μm of the center of the macula, if associated with thickening of the adjacent retina (not residual hard exudates remaining after the disappearance of retinal thickening); (3) a zone or zones of retinal thickening 1 disk area or larger, any part of which is within 1 disk diameter of the center of the macula.

Vascular Damage

Hyperglycemia is the distinguishing feature of diabetes mellitus, which leads to serious cellular damage. Endothelial cells are highly vulnerable to hyperglycemia, because the intracellular regulation of glucose levels is extremely difficult in this cell type. High doses of glucose can alter numerous cellular functions initiating a chain of metabolic reactions usually leading to serious damage of the cell.

Additional risk factors contributing to the pathogenesis of diabetic retinopathy/maculopathy with vascular disruption are hyperlipidemia and systemic hypertension.

Diabetic retinopathy is characterized by abnormal vascular flow, hyperpermeability (resulting in leakage) and/or closure or nonperfusion of capillaries.

The typical feature of early diabetic retinopathy is a change in the anatomical structure and cellular composition of the retinal microvasculature (arterioles, capillaries, and venules).

The following mechanisms are known to cause these changes:

•loss of pericytes (the earliest histologically detectable alteration); the interaction between pericytes and endothelial cells plays an important role in the maturation and maintenance of retinal vessels by initiating the secretion of growth factors and changes in the extracellular matrix;

•damage to vascular endothelial cells;

•thickening of the capillary basement membrane leading to abnormal autoregulation;

•deformation of the erythrocytes;

•increased aggregation of the platelets.

Several factors are known to cause and influence the development of diabetic macular edema due to damage of the retinal vasculature.

•Leukocytes mediate damage to endothelial cells by platelets binding to these cells and induce the expression of adhesion molecules (P-selectin, E-selectin, vascular cell adhesion

molecule 1 and intercellular adhesion molecule 1).

•Leukocytes increase leukostasis, which is one of the first histological changes in

diabetic retinopathy, with it occurring prior to any apparent clinical pathology; adherent leukocytes directly induce endothelial

cell death in capillaries, causing vascular obstruction and vascular leakage.

•Angiogenic factors, mainly the vascular endothelial growth factor (VEGF) cause vascular hyperpermeability by leukocytemediated endothelial injury; this results in the opening of interendothelial junctions and induction of fenestrations as well as the formation of vesiculovacuolar organelles.

•Angiotensin II induces an inflammation in the vascular wall mainly by recruiting leukocytes and initiating their adhesion to

the target tissue. Furthermore, this molecule leads to an increased vascular permeability.

•Advanced glycation end products are believed to enhance the oxidative stress level and induce an inflammatory response by hyperexpression of cytokines and lymphocyte adhesion molecules (vascular cell adhesion molecule 1) as well as vasoactive mediators.

•Sorbitol: hyperglycemia brings on elevated levels of sorbitol through the polyol pathway leading to:

buildup of intracellular sorbitol and fructose, disruption of osmotic balance in the cell, loss of integrity of the blood-retinal barrier (BRB), loss of pericytes due to their sensitivity to polyols and activation of protein kinase C.

•An enhanced production of reactive oxygen intermediates (oxidative stress) occurs due to an elevated oxidative stress level, which is induced by hyperglycemia; as a consequence, inflammation in vascular tissues occurs.

•Matrix changes affect the formation of diabetic macular edema. Matrix

metalloproteinases cause a degradation and modulation of the extracellular matrix. They

belong to a family of zinc-binding, calciumdependent enzymes.

It is likely that matrix metalloproteinases play an important role in various disease stages during the course of BRB dysfunction and breakdown. They cause changes of the endothelial cell resistance and have an influence on the formation and function of the intercellular junctions in the early stages of diabetic retinopathy/maculopathy. Furthermore they are actively involved in processes leading to cell death of both pericytes and endothelial cells.

In diabetes mellitus, early stages of vascular dysfunction are characterized by a breakdown of the BRB. The loss of endothelial cells in retinal vessel walls (inner BRB) is often responsible for the majority of the early BRB breakdown and is the initial site of the damage.

The development of macular edema has also been correlated with the presence of an attached posterior hyaloid. Patients with a posterior vitreous separation are much less likely to develop macular edema.

Venous Occlusive Disease

A central retinal vein occlusion or a branch retinal vein occlusion can cause macular edema, usually in cystoid form. In the latter, macular edema can be observed in cases of the occlusion involving a temporal vein and being located proximal to the venous drainage of the macula.

A leakage is caused by a disruption due to pressure transmitted to the perifoveal capillaries and by turbulent blood flow. An ischemic injury to the capillaries initiates the release of the VEGF, which causes an inflammatory response. This results in a breakdown of the inner BRB.

Two subtypes, ischemic and nonischemic (perfused) macular edema, can be differentiated. Regarding the prognosis for visual acuity, different studies with contradictory results exist (see above).

The Branch Retinal Vein Occlusion Study Group reported that 37% of the patients included

in the study with nonischemic macular edema had an improvement of 2 or more lines after 3 years of follow-up.

The development of blood accumulation in central cystoid spaces is an important clinical finding in venous occlusive disease. It is common in patients suffering from retinal vein occlusion and less common with diabetic, aphakic or pseudophakic macular edema.

Pseudophakic/Aphakic Macular Edema (Irvine-Gass Syndrome)

A CME can develop following cataract surgery and is usually diagnosed 4–10 weeks after surgery. It is well known that damage to the blood-aqueous barrier leads to a release of prostaglandins causing the edema (Gulkilik et al., 2006)9.

A surgical manipulation, which happens during the course of a cataract surgery, always causes an iris trauma. As a result, secondary inflammatory mediators can be liberated by the iris. Once the responsible stimulus (surgery) has been stopped, the physiological healing process is sufficient to suppress the inflammation slowly, but progressively.

In about 90% of macular edemas following cataract surgery, a spontaneous resolution of the edema with an improvement in visual acuity can be observed.

Although a massive leakage can lead to severe irreversible impairment of visual acuity, the patient may not even be aware of visual changes.

Often CME cannot be detected clinically, but the incidence of angiographically detectable CME is as high as 25% after phacoemulsification with no major intraoperative complications.

Another study (Mentes et al., 2003)10 reported an incidence of 9.1%; however, only 1% of these patients experience a decrease in visual acuity. The fixation of the lens to the sulcus is also associated with a higher risk of CME.

The incidence of CME is significantly higher, up to 35.7%, after posterior capsule rupture.

In patients with diabetic retinopathy, cataract surgery may lead to a worsening of a

preexisting macular edema, resulting in a poor visual outcome.

Prevention is possible if the fundus can be visualized and, if not, shortly afterwards. Thus, in patients with diabetes mellitus, an examination using fluorescein angiography and optical coherence tomography should be performed before cataract surgery.

Inflammatory Diseases

In uveitis, macular edema presents mostly in a cystoid form and is a common consequence of the disease. It often persists even after the uveitis has been successfully brought under control.

A macular edema is one of the most common vision-impairing complications of uveitis. It may occur in any type of ocular inflammation (GuexCrosier, 1999)11.

The forms of uveitis which are most commonly associated with macular edema are pars planitis, iridocyclitis, birdshot retinochoroidopathy, sarcoid uveitis and HLA-B27-associated uveitis.

CME can also be observed frequently in Behçet syndrome, Eales disease, Vogt-Koyanagi-Harada syndrome and ocular toxoplasmosis.

Although serous macular exudation has been observed in patients with AIDS-related cytomegalovirus retinitis, macular edema is rare.

Some patients with restored immune competence experience anterior segment and vitreous inflammatory reactions as well as a CME.

In ocular inflammation, an increased production and release of inflammatory mediators such as prostaglandins are the cause of an increased permeability of the parafoveal capillaries and exudation in the macular area.

Nonsteroidal anti-inflammatory drugs and steroids, targeting the arachidonic acid pathway in prostaglandin synthesis, are therefore successfully applied to treat this pathological condition.

Although it is still unknown what factors are responsible for most forms of uveitis, T-cell lymphocytes, the CD4+ subtype in particular, play

a central role in this disease entity (Yeh et al., 2009)12.

Experimental models of uveitis have shown that at the same time as T cells enter the eye, damage in the BRB can be observed.

It is also still unknown whether specific T-cell-secreted cytokines are directly responsible for this mechanism, but it is likely that many of these can damage and cause a breakdown of the BRB.

Phototraumatism

Phototraumatism of the retinal pigment epithelium (RPE) causing a breakdown of the outer BRB often leads to a CME following cataract surgery.

Three mechanisms of light damage can be differentiated:

–thermal lesions result from light absorption by the RPE during the course of the surgery;

–the use of the Q-switched mode of the Nd:YAG laser leads to a mechanical light damage;

–photochemical damage can be caused by the

operating microscope when used for long periods during surgery.

A macular edema after Nd:YAG capsulotomy develops in 0–2.5% of all cases with the incidence increasing if the treatment is performed within the first 3 postoperative months.

Age-Related Macular Degeneration

Age-related macular degeneration can be subclassified into two major forms: the atrophic or dry form and the exudative or wet form.

Atrophic macular degeneration without exudative changes does not generally lead to macular edema.

The exudative form with choroidal neovascularization may cause a serous detachment of the overlying retina, resulting in CME.

The presence of CME is more likely if the serous detachment of the macula has been present for 3–6 months or if the choroidal neovascular membrane has involved the subfoveal region.

Retinal Telangiectasia, Coats Disease

Perifoveal retinal telangiectasia and Coats disease typically show irregularly dilated and incompetent retinal vessels.

These telangiectatic changes can occur at the level of the arterioles, venules or capillaries and cause a cystoid form of macular edema due to heavy leakage.

The closer the cysts are to the macula, the earlier the patient reports symptoms. Symptoms are mainly related to impairment of visual acuity.

Idiopathic juxtafoveal telangiectasia is a milder form of retinal telangiectasia and typically involves the temporal macula. CME is less common than in the previous disorders.

Radiation Retinopathy

Radiation retinopathy is caused by vascular damage from prior radiation treatment to the eye or orbit. A form of macular edema often develops that is quite similar to diabetic macular edema and may manifest as the cystoid form.

The largest study investigating radiation retinopathy included 218 patients treated by proton beam therapy for paramacular tumors. Within 3 years of treatment, 87% of the patients developed macular edema (Guyer et al., 1992)13.

Inherited Dystrophies

The course of retinitis pigmentosa may be influenced by CME due to an increased permeability of the RPE and perifoveal capillaries (Fishman et al., 1977)14. An incidence of 28% has been reported (Sandberg et al., 2008)15.

CME is usually more common in younger patients with minimal RPE disturbances. It can be treated successfully with oral acetazolamide.

Dominantly inherited CME has been described as a clinically distinct form of macular dystrophy usually beginning at approximately 30 years of age. A slow progression over the following decades can typically be observed (Notting and Pinckers, 1977; Hogewind et al., 2008)16, 17.

Characteristics of this syndrome include an early onset and prolonged course of cystoid changes in the macula, followed by atrophy of the retinal tissue in later stages.

Some patients also show a leakage of fluorescein from the optic disk capillaries, a subnormal electrooculogram, an elevated rod dark adaptation threshold, red-green and blue-yellow color deficiencies, normal electroretinogram findings, hyperopia, peripheral pigmentary retinopathy and vitreous opacities.

Tumors

The cystoid form of macular edema can frequently be observed in patients with choroidal melanoma. Three main types of CME can be differentiated: direct, indirect and a combination of both.

Direct involvement may be observed when the melanoma is located subfoveally. An indirect involvement occurs due to subfoveal exudates when the melanoma is distant to the fovea. Indirect foveolar involvement appears without an associated subfoveal tumor or exudates.

The source of CME is at the level of the retinal capillary network and results from intraretinal microvascular abnormalities resembling endothelial cell proliferation.

Other tumors associated with CME are choroidal nevi and the capillary hemangioma.

Drug-Induced Macular Edema

Latanoprost, travoprost and bimotoprost are prostaglandin analogs, which may alter the bloodaqueous barrier in early postoperative pseudophakias or aphakias, thereby causing CME. This phenomenon occurs when these drugs are applied topically.

The drugs themselves are not known to have an influence on the permeability of blood vessels. It has been shown that they stimulate the endogenous synthesis of prostaglandins, which mediate inflammation, thus leading to the breakdown of the blood-aqueous barrier. CME typically resolves

after the drug has been discontinued (Schumer et al., 2000)18.

Some systemic medications, such as nicotinic acid and docetaxel, may also cause a macular edema as well as long-term topical administration of epinephrine and dipivefrine.

Epiretinal Membrane

Epiretinal membranes can cause a surface wrinkling of the underlying retina resulting from contracture of the membrane.

CME is typically caused by a combination of several mechanisms:

•distortion and traction on the surrounding intraretinal vessels resulting in a leakage;

•disturbance of macular microcirculation resulting in a reduced capillary blood flow;

•loss of apposition between the retina and the RPE pump.

Vitreomacular Traction Syndrome

In the vitreomacular traction syndrome, a partial posterior vitreous detachment is combined with a persistent macular adherence and macular traction. A prolonged traction may cause macular edema (fig. 5). A complete vitreomacular separation allows a resolution of the cystoid changes and an improvement in visual acuity.

Acquired Immunodeficiency Syndrome, Immunocompetence

CME has been associated with cytomegalovirus retinitis in patients suffering from acquired immunodeficiency syndrome (AIDS) and immunocompetent patients. At times macular edema develops specifically while the cytomegalovirus retinitis resolves.

CME has also been observed in patients with inactive cytomegalovirus retinitis after immune recovery and improvement of their CD4 counts because of highly active antiretroviral therapy (Kersten et al., 1999)19.

Vascular Components

The Blood-Retinal Barrier and the Role of Proteins

Different factors prevent an accumulation of extracellular intraretinal fluid and proteins by interacting to maintain a balance:

•osmotic forces;

•hydrostatic forces;

•capillary permeability;

•tissue compliance.

The result is that the rate of capillary filtra-

tion equals the rate of fluid removal from the

extracellular retinal tissue. Therefore, the interstitial spaces of the retina can be kept dry in physiological conditions.

The existence of a BRB formed by intercellular junctions is the precondition required to maintain this physiological status. These junctions are transmembrane molecules connecting cells with each other. They are linked to special cytoskeletal linker molecules. Furthermore, several regulatory molecules are present at the site, regulating the interaction with the cytoskeleton (fig. 6).

The role of the BRB is the separation of blood from the surrounding retinal tissue. In addition, this barrier has to control the protein and the cell passage from the blood into these tissues as well as the leukocyte extravasation when inflammation occurs.

In the inner retinal circulation, the BRB is formed by tight junctions (zonula occludens). Intercellular communication is realized by adherent junctions (zonula adherens) and gap junctions (macula communicans) joining the endothelium

of retinal capillaries. The molecular composition of these intercellular junctions is different along the vasculature of the retina.

In the outer retinal circulation, the tight junctions between the pigment epithelium cells maintain the BRB, as well as adherens junctions and desmosomes (macula adherens).

The BRB maintains the stability of the environment of ocular neurons and photoreceptors and ensures their physiological functions. Apart from these structures there are no other anatomical barriers to prevent water movement in the retina.

The interstitial pathway from the vitreous cavity to the subretinal space is long and ends with zonulae adherentes, forming the external limiting membrane (ELM). The internal limiting membrane (ILM) has, according to recent studies, probably no significant influence on water movement (Rotsos and Moschos, 2008)4. This means that surgical removal of the ILM would neither increase nor decrease fluid movement.